Controlling Nutritional Status (CONUT) Score is a Prognostic Marker in III-IV NSCLC Patients Receiving First-line Chemotherapy


 Background: To investigate the prognostic impact of the controlling nutritional status (CONUT) score in non-small-cell lung cancer (NSCLC) patients receiving first-line chemotherapy.Methods: We retrospectively reviewed 278 consecutive patients undergoing chemotherapy for stage III-IV NSCLC between May 2012 and July 2020. CONUT score was calculated by incorporating serum albumin, total cholesterol, and total lymphocyte count. The clinicopathological features and follow-up data were evaluated to compare the CONUT score with other prognostic indices, such as the systemic immune-inflammation index (SII) and prognostic nutritional index (PNI), in patients with NSCLC. Results: Applying cut-offs of ≥3 (CONUT), ≥443.607 (SII), and ≥49.05 (PNI). The high CONUT group had a significantly shorter progression-free survival and overall survival than the low CONUT group. A high CONUT score was significantly associated with older age, worse ECOG PS, advanced clinical stage, and lower PNI (all P < 0.05). In the univariate analysis, higher SII, higher CONUT, advanced clinical stage and lower PNI were associated with worse PFS (P<0.05). Worse ECOG PS, higher SII, higher CONUT, advanced clinical stage and lower PNI were associated with worse OS (P<0.05). In multivariate analysis, SII and CONUT score were independently correlated with PFS (P<0.05), while PNI and CONUT score were independently correlated with OS (P<0.05).Conclusion: CONUT score is an independent prognostic indicator of poor outcomes for patients with stage III-IV NSCLC and is superior to the SII and PNI in terms of prognostic ability.Trial registration: retrospectively registered.


Background
Non-small-cell lung cancer (NSCLC) is the most common cause of cancer-related death and a major public health problem worldwide, accounting for more than one million deaths annually. [1,2] Over the last 20 years, the treatment strategies for advanced and metastatic NSCLC have dramatically changed. Although the treatments in lung cancer have made great progress, [3] more effective treatment strategies must consider patient selection and evaluate the prognosis of patients with NSCLC. Recently, there has been increasing interest in identifying prognostic factors for tailored treatment.
Recently, patient immunonutritional status has been linked to treatment outcome. Immunonutritional status is an important feature of the tumour microenvironment and is associated with poor prognosis of various types of tumours. [4,5]Prognostic nutritional index (PNI) is a proven scoring system based on immunonutritional status that allows an estimation of treatment tolerability and cancer progression. [6] In ammation is also reported to be associated with cancer prognosis. Haematological in ammatory parameters such as neutrophils, lymphocytes, monocytes, and platelets can re ect systemic and focal in ammation and have important value in predicting the prognosis of tumours, including NSCLC. [7,8] The Controlling Nutritional Status (CONUT) score is a new scoring system for patient immunonutritional status that has attracted substantial attention and is reported to be associated with clinical outcomes in various malignancies. Similar to the PNI and systematic in ammation index (SII), [9,10] the CONUT score is easily obtained and calculated from three clinical parameters: serum albumin, total cholesterol, and total lymphocyte count. [11] It has been reported that the CONUT score can be a predictive or prognostic marker in many types of cancers. For NSCLC, some reports have shown that the CONUT score is useful for predicting long-term outcomes of surgery and immune therapy. [12][13][14] However, few studies have reported whether the CONUT score is associated with the prognosis of NSCLC patients treated with chemotherapy.
The aim of this retrospective study was to determine whether prechemotherapy CONUT score could be a useful predictor of survival in patients with NSCLC and to compare the accuracy of the CONUT score, PNI and SII as predictors of the survival rate of such patients.

Patients
We retrospectively enrolled 278 patients diagnosed with advanced NSCLC who regularly received DP (docetaxel plus cisplatin), GP (gemcitabine plus cisplatin , NP (vinorelbine plus cisplatin), PC (pemetrexed plus cisplatin ) and TP (paclitaxel plus cisplatin) chemotherapy regimens at the A liated Hospital of Xu Zhou Medical University from January May 2012 and July 2020.
The inclusion criteria were as follows: (1) NSCLC was pathologically diagnosed; (2) NSCLC was stage III or IV according to the American Joint Committee on Cancer (AJCC) 8th edition; (3) the patient received chemotherapy for more than two cycles without a combination of targeted therapy, radiation therapy and immune therapy; (4) the patient had no other cancer history and laboratory test results were obtained before treatment.
The exclusion criteria were as follows: (1) patients with missing or incomplete data; (2) patients who underwent surgery, radiotherapy, immunotherapy before standard chemotherapy protocols, (3) patients who had obvious fever and pneumonia before chemotherapy.
This retrospective study was approved by the ethics committee of the A liated Hospital of Xu Zhou Medical University.
Data collection and follow-up Data, including age, sex, histological subtype, stage, smoking status, chemotherapy regime, Eastern Cooperative Oncology Group Performance Status (ECOG PS) scores, routine blood parameters and biochemical pro les, were collected retrospectively from individual medical case notes, electronic patient records and pathology reports. Blood samples were obtained and assayed within 2 weeks before chemotherapy. CONUT scores were summarized using the serum albumin concentration, peripheral lymphocyte counts and the total cholesterol concentration, as described in Table 1. The following formula was used to calculate PNI and SII. PNI: albumin (g/L) × total lymphocyte count × 10 9 /L. SII: platelet count × neutrophil count/lymphocyte count. [9,15] Follow-up was performed every 3 months. All patients were monitored either until July 2020 or until death. The median follow-up time was 24 months (range, 3-75 months). PFS was de ned as the interval from treatment initiation until disease progression or death. OS was de ned as the interval from treatment initiation until the date of death or the date of last follow-up for patients who had not died before the censor date. CONUT score (total) 0-1 2-4 5-8 9-12

Statistical analysis
The associations between CONUT score and clinicopathological characteristics were analysed using χ2 tests. The patients were classi ed into two groups based on receiver operating characteristic (ROC) curves. To evaluate whether the CONUT score, PNI and SII have value for prognosis, we used ROC curves. Survival analysis was performed using Kaplan-Meier method. The differences between the survival curves were compared by log-rank test. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% con dence intervals (CIs). A P value <0.05 was considered to indicate statistical signi cance. The results were analysed using SPSS 21.0.

ROC analysis
ROC analysis was performed to identify the optimal cut-off point with the highest sensitivity and speci city, which  characteristics of all patients are detailed in Table 2. A high CONUT score was signi cantly associated with older age, worse ECOG PS, advanced clinical stage, and lower PNI (all P < 0.05)

Prognostic value of SII, PNI, and CONUT
In the present study, we found that CONUT 3 before treatment was associated with longer PFS and OS ( Figure 2).
After strati cation by TNM stage, the prognostic signi cance of the CONUT score was also maintained in patients with stage III and stage IV disease. (Figure 3) A univariate analysis of the factors associated with PFS indicated that higher SII, higher CONUT, advanced clinical stage and lower PNI were factors associated with worse survival (Table 3). A multivariate analysis indicated that SII and CONUT were signi cant independent prognostic parameters for PFS (Table 4).  In Cox hazard analyses, univariate analysis showed that ECOG PS, SII, CONUT score, clinical stage and PNI were signi cantly associated with OS (Table 3). After the exclusion of variables that showed no impact on OS in univariate analysis, Cox multivariate regression analysis was performed, which identi ed only PNI and CONUT score as independent prognostic factors of OS (Table 4).

Discussion
In the present study, we established an immune-nutrition-based prognostic index (CONUT) based on serum albumin, total cholesterol, and total lymphocyte count and demonstrated the prognostic value of CONUT in III-IV NSCLC. To our knowledge, this is the rst report investigating the prognostic value of CONUT and comparing the superiority between nutrition-based indices and in ammation-based indices in patients with advanced NSCLC treated with chemotherapy. Moreover, the results indicated that CONUT score was associated with age, ECOG PS, clinical stage, and PNI. Signi cantly, without considering the tumour stage, CONUT independently predicted the prognosis of NSCLC patients. Compared with low CONUT scores, high CONUT scores predicted shorter PFS and OS.
As mentioned above, the prognostic nutritional index (PNI), as a nutrition-based index, which was calculated from the serum albumin concentration and the total peripheral lymphocyte count, has been reported to correlate with survival in NSCLC patients. [16] It is not di cult to see that the two indices of PNI are covered by the CONUT scoring system. The serum albumin concentration is a common nutritional status indicator that can be in uenced by many other factors, such as liver function, in ammation, infection, dehydration and so on. [17,18] Hence, to reduce the weight of serum albumin, some scholars proposed adding plasma cholesterol levels to optimize the PNI scoring system. [19]. In addition, cytokines and CRP also modulate the production of albumin. [17,18] As cholesterol plays a crucial role in in uencing cell membrane uidity, cholesterol affects the mobility of cell surface receptors and their ability to transmit signals. Moreover, serum cholesterol levels in uence caloric intake. [19] Lymphocytes play a key role in initiating cellular immunity, and high numbers of in ltrating lymphocytes are associated with good prognosis. [20,21] Therefore, the combination of these three parameters could balance the impact of each parameter.
In ammation-based indices also act as oncological prognosis biomarkers. A series of in ammation indices, such as NLR, PLR, LMR and SII, showed positive correlations with poor survival outcome in patients with lung cancer[18, 22,23]. Some reports have also illuminated that the SII is a superior prognostic factor for survival outcome compared to the NLR and PLR [24]; therefore, we selected the SII as the representative in ammation prognostic index. It is not hard to see that serum albumin and cholesterol are not only nutrition indices but also in ammatory indices.
However, the SII is a pure in ammatory index based on neutrophils, lymphocytes, and platelets and is more easily affected by external factors, such as pneumonia. Furthermore, separate analyses of the prognostic value of the SII in patients with stage III NSCLC showed no signi cant effects on either PFS or OS, which, from another perspective, illustrates that the CONUT score is superior to the SII (p all >0.05, data not shown). Therefore, we hypothesize that CONUT is a superior prognostic biomarker that not only re ects the features of tumour cells but also re ects the nutritional status of patients.
The present study has certain limitations. First, this is a retrospective analysis; hence, there are several potential factors that might have in uenced the studied results, such as lipid-lowering agents. Second, data for all patients were collected from a single institute, and the number of patients was relatively small. Third, different nutritional support in the process of chemotherapy might have confounded our results. Therefore, a multi-institutional investigation, especially a prospective validation study, is needed to con rm the results.

Conclusion
The present study indicates that CONUT is an independent prognostic indicator of poor outcomes for patients with stage III-IV NSCLC and is superior to SII and PNI in terms of prognostic ability. For this type of study, formal consent is not required.

Consent for publication
We declare that the manuscript, including related data, gures and tables has not been published previously and that the manuscript is not under consideration elsewhere.

Availability of data and materials
All data included in the present study were presented in the main manuscript

Competing interests
The authors have stated that they have no con icts of interest.

Funding
Not applicable.
Authors' contributions YZ and ZQZ conceived and designed the experiments and were responsible for data analysis and writing the manuscript. FFK were responsible for providing the clinical samples. FFK and YZ was responsible for data